SARS-CoV-2 N-protein induces the formation of composite -synuclein/N-protein fibrils that transform into a strain of -synuclein fibrils

The presence of deposits of alpha-synuclein (alpha S) fibrils in the cells of the brain is a hallmark of several alpha-synucleinopathies, including Parkinson's disease. As most disease cases are not familial, it is likely that external factors play a role in the disease onset. One of the external factors that may influence the disease onset is viral infection. It has recently been shown in in vitro assays that in the presence of SARS-Cov-2 N-protein, alpha S fibril formation is faster and proceeds in an unusual two-step aggregation process. Here, we show that faster fibril formation is not due to the SARS-CoV-2 N-protein-catalysed formation of an aggregation-prone nucleus. Instead, aggregation starts with the formation of a population of mixed alpha S/N-protein fibrils with low affinity for alpha S. Mixed amyloid fibrils, composed of two different proteins, have not been observed before. After the depletion of N-protein, fibril formation comes to a halt, until a slow transformation into fibrils with characteristics of a pure alpha S fibril strain occurs. This transformation into a strain of alpha S fibrils subsequently results in a second phase of fibril growth until a new equilibrium is reached. We hypothesize that this fibril strain transformation may be of relevance in the cell-to-cell spread of the alpha S pathology and disease onset. SARS-CoV-2's N-protein accelerates alpha S aggregation, initially forming a composite alpha S/N-protein amyloid fibril strain that in time evolves into a strain of alpha S fibrils which can likely propagate without N-protein, even in uninfected cells.